HEAT-INDUCED MEMBRANE DAMAGE COMBINED WITH ADRIAMYCIN ON PROSTATE CARCINOMA PC-3 CELLS - CORRELATION OF CYTOTOXICITY, PERMEABILITY AND P-GLYCOPROTEIN OR METALLOTHIONEIN EXPRESSION

Objective To assess heat-induced membrane damage in a prostate cancer cell line when combined with adriamycin treatment. Materials and metho ds The changes in intracellular adriamycin accumulation, cell prolifer ation and cell-cycle fractions were examined after human prostate carc inoma PC-3 cells were exposed to heat and/or further treatment with ad riamycin. Proliferation and the cell cycle were determined using adher ent cell analysis and sorting laser cytometry (ACAS) or flow cytometry . P-glycoprotein (PGP) and metallothionein (MT) expression, which may have a physiological role in the transport of or reduction in cytotoxi city of some anticancer drugs, were also analysed after cells were exp osed to heat, using immunohistochemical or flow cytometric methods. Re sults There was a significant increase in intracellular adriamycin acc umulation, related to both influx (P<0.05) and efflux (P<0.01), in cel ls treated with adriamycin, especially after heating them at 44 degree s C for 1 h. There was a significant decrease in cell proliferation of preheated cells when exposed to adriamycin, especially at 44 degrees C (P < 0.05). In the cell-cycle analysis, cells preheated at 44 degree s C showed partial accumulation in the debris or apoptotic fraction at 24 h, and many cells accumulated in these fractions at 48 h. There wa s significantly less PGP or MT expression in cells preheated at 44 deg rees C than in control cells or cells preheated at 41 degrees C (P<0.0 1). This reduction in PGP or MT level by heating may inhibit drug effl ux and thus increase intracellular drug level at elevated temperatures . Conclusions These results suggest that hyperthermia may damage the d rug-exclusion mechanism in these cells and thus increase the effective ness of drug action.